Project Summary/Abstract 1 This proposal details a 5-yr plan to prepare the candidate, Juan C. Cardet MD, for a career as an 2 independent, translational investigator positioned to impact our understanding of asthma. The aim is to clarify 3 the relationship between enterolactone and asthma through complementary clinical and basic strategies. 4 Lignans are dietary, plant-derived chemicals with anti-inflammatory and antioxidant properties. Enterolactone 5 is the end product of human gut bacterial metabolism of lignans. Differences in gut microbiome composition 6 categorize patients into high- vs. low-enterolactone producers. This group reported concentration-dependent 7 inverse associations between enterolactone and asthma in a nationally-representative cohort (NHANES); but 8 this study is limited by its cross-sectional design and incomplete clinical characterization. We hypothesize 9 that enterolactone's inverse relationship with asthma is driven by its anti-inflammatory and anti- 10 oxidative properties. The candidate will clarify whether enterolactone has a clinically-evident relationship 11 with asthma by analyzing data from the NHLBI Severe Asthma Research Program's (SARP) prospective 12 study. As a founding partnership in SARP, our group has access to stored biospecimens and participants' 13 clinical, biochemical, and physiological data collected during 3 years of follow-up. Further, the candidate 14 will employ in vitro and in vivo approaches to determine enterolactone's effects on human airway structural 15 cells and murine models of asthma. Preliminary data by Cardet et al suggest that enterolactone may have 16 anti-inflammatory effects on A549 human airway epithelial cells, observations this group will extend through 17 this proposal. Clinical findings will steer the focus of laboratory experiments, and reversely, discoveries at the 18 bench will generate clinical questions. At this project's conclusion, the candidate will be skillful with (1) 19 sophisticated biostatistical analyses on clinical datasets such as SARP's; and with designing, conducting, and 20 interpreting experiments on (2) airway structural cells (3) and murine models of asthma. 21 During the award period, the candidate will leverage his clinical experience with asthma, regular exposure to 22 NIH research networks, and structured academics at the HSPH's MPH program. This training will allow him to 23 transition to independence during the 4-5th years of the award. Dr. Cardet will work under the 1 mentorship of 24 Dr. Elliot Israel, an expert in translation asthma research with an excellent mentoring record. He will have as 25 co-mentors Drs. Quan Lu and Stephanie Shore, who will train Dr. Cardet to master the basic experiments 26 described herein (see `Research Strategy, Aim 2'). Further, Dr. Cardet has assembled a team of 27 extraordinary physician-scientists (Drs. Joshua Boyce, Bruce Levy, and Wanda Phipatanakul), who have 28 committed their time and expertise to assist his career development and research goals. Their mentorship, the 29 scientific-clinical environment at BWH and HSPH, and the proposed research goals and career development 30 plan will position the candidate to establish himself as an independent translational asthma researcher.